International Journal of Applied Pharmaceutics
ISSN- 0975-7058
Vol 16, Issue 2, 2024
Original Article
FORMULATION AND EVALUATION OF SUSTAINED-RELEASE FLOATING MATRIX TABLETS OF
VALGANCICLOVIR HYDROCHLORIDE
YASHAVANTH G.*
, PRAKASH GOUDANAVAR
, MALLAMMA T.
, SANTHOSH FATTEPUR
Department of Pharmaceutics, Sri Adichunchanagiri College of Pharmacy, BG Nagar, Karnataka 571488, India
*Corresponding author: Yashavanth G.; Email: yashavanthg1995@gmail.com
Received: 12 Sep 2023, Revised and Accepted: 10 Jan 2024
ABSTRACT
Objective: The present study aimed to formulate and evaluate the formulated sustained-release floating matrix tablets of valganciclovir
hydrochloride to produce a stable and bioavailable dosage form.
Methods: The tablets were prepared using hydrophilic and hydrophobic polymers such as ethyl cellulose, Hydroxy-propyl methylcellulose (HPMC),
and Povidone. The formulations were subjected to evaluation characteristics such as drug content, hardness, friability, float ing lag time, total
floating time, and In vitro drug dissolution studies.
Results: The formulation composition and method of manufacturing are novel for this particular active moiety and robustness was assessed using a
central composite design. All the formulation trials exhibited more than 90% of drug release in 12 h duration, with a floating lag time of more than
11 h, and drug content was found more than 90% across the batches. The hardness and friability profiles were found to be uniform across the
batches. The preliminary evaluation confirms the received drug is pure and FTIR results show that the drug and excipients are compatible. The
hardness and friability profiles were found consistent across the batches. All the formulation trials of central composite de sign have shown more
than 90% of drug release in 12 h duration, with a floating lag time of more than 11 h, and drug content was found more than 90% across the
batches.
Conclusion: The formulated valganciclovir hydrochloride sustained release floating matrix tablets showed an increased GRT with a sustained
release for 12 h, thereby allowing a better window for absorption and consequently improving the drug's therapeutic effect.
Keywords: Gastroprotective, Valganciclovir hydrochloride, AIDS, DOE
© 2024 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/)
DOI: https://dx.doi.org/10.22159/ijap.2024v16i2.49521 Journal homepage: https://innovareacademics.in/journals/index.php/ijap
INTRODUCTION
Human cytomegalovirus (CMV) earns its name from the characteristic
cytomegalic appearance of intranuclear inclusions in infected cells, an
appearance first described in 1881. As a member of
the Herpesviridae family, human herpes virus 5 (HHV 5), or CMV, is a
double-stranded DNA virus capable of a wide spectrum of diseases in
humans [1].
Among many anti-viral drugs, valganciclovir hydrochloride is a
potent antiviral agent that has been approved for the treatment of
cytomegalovirus diseases like CMV retinitis in patients with
acquired immunodeficiency syndrome (AIDS) and for the prevention
of cytomegalovirus (CMV) disease in kidney, heart, and kidneypancreas transplantation. Valganciclovir hydrochloride is the Lmonovaline ester of ganciclovir and is a stable prodrug of ganciclovir
with improved absorption. Valganciclovir hydrochloride is described
in detail in United States patent No. 6,083,953 [2].
Oral administration is the most versatile, convenient, and commonly
employed route of drug delivery for systemic action. Indeed, for
controlled release systems, the oral route of administration has
received more attention and success because gastrointestinal
physiology offers more flexibility in dosage form design than other
routes [3]. There has been considerable research over the last decade
on the possibility of controlled and site-specific delivery to the GIT by
controlling the gastrointestinal transit of orally administered dosage
forms using gastro retentive drug delivery system (GRDDS). Such
GRDDS possess the ability to retain the dosage forms in the
gastrointestinal tract (GIT) particularly in the stomach for a long
period [4]. GRDDS perfectly increases the drugs’ gastric retention
times and their bioavailability increases [5]. Gastric retention systems
are such systems that increase the gastric retention time of the dosage
form at the stomach and upper parts of the small intestine and are
suitable for the drugs having site-specific absorption from the above
sites [6]. gastro retentive drug delivery systems (GRDDS) are lowdensity systems that have sufficient buoyancy to float over the gastric
contents and remain in the stomach for a prolonged period. are
preferred as they are economical and have improved patient
compliance and they are advantageous for drugs absorbed from the
stomach [7]. To formulate a successful gastroprotective drug delivery
system various technologies developed until now, i.e., high density
(sinking), floating, bio-or mucoadhesive, expandable, super porous
hydrogel, magnetic systems, etc [8]. Floating dosage forms may be
made as tablets or capsules by using appropriate excipients and
including gas-generating agents, which give the dosage form buoyancy
in gastrointestinal fluids [9]. The present study aimed to formulate and
evaluate the formulated sustained release floating matrix tablets of
valganciclovir hydrochloride to produce a stable and bioavailable
dosage form.
MATERIALS AND METHODS
Materials
Valganciclovir HCl (99.98% purity), Magnesium stearate, and talc
were obtained as a gift sample from Strides pharma., Bangalore,
India. Microcrystalline cellulose, Ethyl cellulose, and Povidone-k-30
were obtained from Stabicon Life Sciences, Bangalore India. Sodium
bicarbonate and colloidal silicon dioxide are obtained from Shilpa
Medicare, Dabaspete, India.
Methodology
Melting point evaluation
The melting point of an organic solid can be determined
by introducing a tiny amount into a small capillary tube, attaching
this to the stem of a thermometer centered in a heating bath, heating
the bath slowly, and observing the temperatures at which melting
begins and is complete [10].
Solubility test
In general, the solubility test for the drug valganciclovir was
performed by using various solvents, which include distilled water,
Y. G. et al.
Int J App Pharm, Vol 16, Issue 2, 2024, 195-201
ethanol, dimethyl sulfoxide (DMSO), methanol, ethanol: water (1:9),
and isopropyl alcohol.
chemical composition of the drug after combining it with the
excipients.
Construction of calibration curve
Drug content
The 100 mg of Valacyclovir Hydrochloride was dissolved in 100 ml
of 0.1N HCl. A series of dilutions containing 5,10,15,20 and 25 μg/ml
of drug per ml of solution were prepared. The absorbance of the
above dilutions was measured at 254 nm by using a UVspectrophotometer. The graph was plotted by taking concentration
on the X-axis and absorbance on the Y-axis which gives a straightline linearity of the standard curve was assessed from the square of
correlation coefficient (R2), which was determined by least-square
linear regression analysis [11].
10 tablets were dissolved in 0.1N Hcl solution at room temperature
and absorbance was taken at 254 nm by using a UV
spectrophotometer to determine the amount of valganciclovir
hydrochloride [12].
Drug-excipient compatibility study
Compatibility studies were carried out to know the possible
interactions between valacyclovir HCl and the excipients used in the
formulation. Physical mixtures of drugs and excipients were
prepared to study the compatibility using the FTIR. The
investigations were carried out to denote the changes in the
Formulation of valganciclovir hydrochloride tablets
Wet granulation method
All the materials are dispensed as per BOM. Valganciclovir
hydrochloride and sodium bicarbonate are sifted through #40mesh
(step 1). The Hydroxypropyl methylcellulose (HPMC K15M), ethyl
cellulose, and microcrystalline cellulose (MCC) are sifted through
#30mesh (step 2). Step 1 and Step 2 are blended manually in a 2 kg
polybag for 5 min (Step 3). The dispensed binder is dissolved in the
required quantity of purified water by using a remi stirrer at
optimum rpm. The step 3 is transferred to RMG.
Table 1: Mixing parameters monitored during the process
Parameter
Dry mixing
Binder addition
Kneading
Impeller rpm
150.00
150.00
150.00
Chopper rpm
off
750.00
750.00
Time in min
5.00
30.00
2.00
LOD @105 °C
4.5
NAP
NAP
Note: The amount of water consumed for granulation is 25 gm (12.5%).
Table 2: Drying parameters monitored during process
S No
1
2
3
4
5
6
Time in min
Initial
After 20
After 30
After 40
After 45
After 50
Inlet temp (°C)
50.00
65.00
65.00
50.00
50.00
50.00
Airflow (cfu)
75.00
75.00
65.00
55.00
50.00
50.00
The dried granules are milled with a 1.0 mm grated screen at
900rpm using a co-mill, the milled granules are sifted through #12
mesh (step 4). Talc and colloidal silicon dioxide are passed through
#60mesh, then added for step 4 and blended manually for 2 min
(step 5). The magnesium stearate is passed through #60 mesh, then
added for step 5 and blended manually for 5 min.
Product temp (°C)
21.80
24.40
27.30
28.80
30.70
31.20
LOD @105 °C
NAP
7.80
6.50
5.60
4.40
4.00
RESULTS AND DISCUSSION
Melting point
Compression parameters
The melting point is determined using the capillary tube for
valganciclovir hydrochloride to ensure the received drug is pure and
has the same chemical entity. The melting point was found 164 °C,
which is matching with the theoretical range [14].
The 15 mm size and plain concave punch are used for compression.
Solubility analysis
In vitro drug dissolution studies
The solubility of valganciclovir hydrochloride is performed using
different solvents and in a mixture of solvents. As per the
information provided in the US patent, valganciclovir hydrochloride
has shown maximum solubility in 0.1N Hcl solution [2].
In vitro release studies of the prepared formulations were carried
out using USP Dissolution test apparatus II. A 900 ml of 0.1 N HCl
solution was used as dissolution medium which is maintained at a
temperature of 37±0.5 °C and the paddle was rotated at 50 RPM.
Aliquots of 5 ml each of the dissolution media were withdrawn using
a syringe fitted with a prefilter at appropriate time intervals and
immediately replaced with 5 ml of fresh medium maintained at
37±0.5 °C. The absorbance of samples was measured at 254 nm after
suitable dilutions with the medium using a UV Spectrophotometer.
Determination of floating lag time and total floating time
The floating lag time (FLT) is the time taken for a tablet to rise
on a medium surface, and the total floating time (TFT) is the
floating duration that a tablet remains on the surface. To
determine the floating lag time, tablets were put on 100 mL of
0.1 N HCL in a beaker, and the time is required for a tablet to rise
on the surface was measured. Then, the duration of each
formulation that remained on the surface was determined as
total floating [13].
Table 3: The solubility profile of valganciclovir hydrochloride
Solvent
0.1N Hydrochloric acid
Water
Phosphate Buffer of pH at 7.4
Methanol/DMSO
Solubility status
Freely soluble
Sparingly soluble
Sparingly soluble
Slightly soluble
Determination of λmax
From 0.1N Hcl with valganciclovir working standard solution, 5 ml
was pipette out into a 10 ml volumetric flask, and the volume was
made up to the mark with 0.1N Hcl to prepare a concentration of
50µg/ml. Then the sample was scanned in a UV spectrophotometer in
the range 400-200 nm using 0.1N Hcl as a blank and the wavelength
196
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Int J App Pharm, Vol 16, Issue 2, 2024, 195-201
corresponding to maximum absorbance (λmax) was found to be 254
nm. The obtained absorbance maximum was found similar to the
theoretical value determined by multiple researchers [15].
Drug-excipient compatibility
FT-IR study was carried out to check any possible interactions
between the drug and the Inactive ingredients. Pure drug was mixed
with Inactive ingredients with respect ratio which is proportional to
the formulation composition and checked for any interaction
present. The major FTIR peaks of the drug were retained in the FTIR
physical mixtures. The study results revealed that no major
interaction between the selected drug and inactive ingredients.
Formulation development
The formulation of sustained-release floating matrix tablets of
valganciclovir hydrochloride is carried out using dry granulation
and direct compression techniques in the initial stages. However,
due to hardness and friability issues the wet granulation method is
adopted and the formula is optimized using different binders and
controlled-release polymers. To study the robustness of
formulation, the design of experiment (DOE) trials was carried out
by using a central composite design. The F1 and F10 are the
control formulations used as bracketing controls in the design of
experiment (DOE) trials.
Fig. 1: FTIR spectra for valganciclovir hydrochloride
Fig. 2: FTIR spectrum of valganciclovir hydrochloride and hydroxy propyl methyl cellulose
Fig. 3: FTIR spectrum of valganciclovir hydrochloride and all inactive ingredients
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Table 4: Formulation with central composite design
Formulation with central composite design
Ingredients
Valganciclovir hydrochloride (mg/tab)
Microcrystalline cellulose (mg/tab)
Povidone K 30 (mg/tab)
Ethyl cellulose (mg/tab)
HPMC K15 (mg/tab)
Sodium bicarbonate (mg/tab)
Colloidal silicon dioxide (mg/tab)
Talc (mg/tab)
Magnesium stearate (mg/tab)
Total (mg)
F1
450.00
88.00
16.00
32.00
100.00
96.00
4.00
6.00
8.00
800.00
F2
450.00
87.68
16.32
32.00
100.00
96.00
4.00
6.00
8.00
800.00
F3
450.00
88.32
15.68
32.00
100.00
96.00
4.00
6.00
8.00
800.00
F4
450.00
87.36
16.00
32.64
100.00
96.00
4.00
6.00
8.00
800.00
F5
450.00
88.64
16.00
31.34
100.00
96.00
4.00
6.00
8.00
800.00
F6
450.00
86.00
16.00
32.00
102.00
96.00
4.00
6.00
8.00
800.00
Table 5: Formulation with central composite design
Formulation with central composite design
Ingredients
Valganciclovir hydrochloride (mg/tab)
Microcrystalline cellulose (mg/tab)
Povidone K 30 (mg/tab)
Ethyl cellulose (mg/tab)
HPMC K15 (mg/tab)
Sodium bicarbonate (mg/tab)
Colloidal silicon dioxide (mg/tab)
Talc (mg/tab)
Magnesium stearate (mg/tab)
Total (mg)
F7
450.00
90.00
16.00
32.00
98.00
96.00
4.00
6.00
8.00
800.00
F8
450.00
86.08
16.00
32.00
100.00
97.92
4.00
6.00
8.00
800.00
Hardness and friability evaluation profiles for formulations of
central composite design
The hardness is tested with an erweka hardness tester and
friability is tested with Roche friability apparatus. The results
F9
450.00
89.92
16.00
32.00
100.00
94.08
4.00
6.00
8.00
800.00
F10
450.00
87.84
16.00
32.00
100.00
96.00
4.00
6.00
8.16
800.00
F11
450.00
88.16
16.00
32.00
100.00
96.00
4.00
6.00
7.84
800.00
F12
450.00
88.00
16.00
32.00
100.00
96.00
4.00
6.00
8.00
800.00
were found consistent across the batches. The hardness profile
was found more stable enough to withstand the friability and to
provide a controlled release profile from all the batches of central
composite design. The assay results were found uniform across the
formulation batches.
Table 6: Hardness, friability, and drug content profiles
Formulation
F1
F2
F3
F4
F5
F6
F7
F8
F9
F10
F11
F12
Hardness (Newton)
201.04±3.92
204.71±5.18
197.39±3.91
203.16±6.67
200.98±6.39
207.44±5.36
196.38±3.71
201.25±3.84
202.68±7.80
210.37±4.75
206.43±6.63
204.27±3.44
Friability (%)
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
Assay (mg/tab)
97.00-103.00%
Note: (mean±SD n=3)
Table 7: Dissolution profiles for formulations of central composite design
Time in min
F1
F2
F3
F4
F5
F6
F7
F8
F9
F10
F11
F12
Average
% SD
60 min (% CDR)
12.04±1.58
11.87±2.42
12.82±2.85
12.11±1.62
13.62±4.21
11.20±3.24
13.22±2.02
12.52±2.63
13.21±2.86
12.50±3.01
13.12±2.41
13.02±1.21
12.60
0.70
120 min (% CDR)
22.26±3.06
22.01±3.63
23.45±2.89
23.20±4.15
25.16±3.55
21.04±4.06
24.70±4.25
23.07±2.41
26.21±3.33
21.08±3.97
23.56±3.45
22.79±2.33
23.21
1.57
240 min (% CDR)
37.22±2.85
35.52±3.52
38.23±2.25
37.55±3.65
39.50±4.22
36.22±5.03
35.34±3.45
36.89±3.61
37.86±2.88
36.45±3.24
37.89±3.85
36.87±3.71
37.13
1.18
480 min (% CDR)
78.95±4.55
76.25±3.25
78.88±4.02
76.23±3.85
79.21±2.62
77.89±3.07
75.09±4.01
77.22±3.96
77.95±3.77
77.04±4.54
78.62±4.14
77.50±2.10
77.57
1.27
720 min (% CDR)
97.21±4.02
96.20±3.29
96.11±2.98
94.21±3.55
98.44±4.14
95.01±3.78
96.23±3.33
96.23±5.06
96.74±3.87
95.26±3.64
98.63±2.73
96.55±3.98
96.40
1.28
Note: *The % standard deviation is considered from an average of 12 batches and from each batch 6 tablets are tested for dissolution (mean±SD, n=6).
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Int J App Pharm, Vol 16, Issue 2, 2024, 195-201
Dissolution profile for formulations of central composite design
The formulation design is made from the theoretical aspect of the central
composite design to evaluate the robustness of the formulation
composition. The functional excipient povidone K 30 is varied
between+2% to-2% from the target concentration to evaluate the
hardness and friability profile. The HPMC K15, magnesium stearate, and
ethyl cellulose are varied between+2% to-2% to evaluate the release
profile of valganciclovir hydrochloride sustained release floating matrix
tablets. The release profile was found to be exceptional across the
batches. The formulated tablets have shown sustained release over 12 h
by releasing>90% drug. This indicates minor variation in composition
from the control formulation has no impact on the release profile
thereby product quality. High concentration of polymer influences the
formation of swollen mass that restricted the rate of diffusion into the
matrix, which may result in retardation the drug release (16). As per the
reference quoted here, the same observation was found with our
formulation, which has high polymer content (F6).
Fig. 4: Dissolution profile for HPMC K15 variable composition
Fig. 5: Dissolution profile for formulation DOE
Dissolution profile on process optimization
The formulation is carried out to study the robustness of process
design by varying the critical process parameter of binder addition
rate to±1 min and the release profile is evaluated; the analytical
results were found that there is no meaningful difference observed
in the release profiles when comparing target formulation. However,
the binder addition rate is not impacting the quality of the product
but it's considerably increasing the drying time for 10-15 min; hence
the addition rate should be maintained to avoid loss of time.
Fig. 6: Drug release profile formulation with variable process parameters
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Determination of floating lag time and total floating time
The tablets were prepared by effervescent technique using sodium
bicarbonate as a gas-generating agent. Sodium bicarbonate induced
carbon dioxide generation in the presence of dissolution of a medium
(0.1N Hcl). The gas generated is trapped and protected within the gel,
formed by the hydration of the polymer, thus decreasing the density of
the tablet. As the density of the tablet falls below 1 g/ml, the tablet
becomes buoyant (17). The effect of sodium bicarbonate on buoyancy
of the tablets was evaluated by using it at 2 different level but since
difference is minimal, no major difference has been observed. The
selected concentration of sodium bicarbonate is more enough to
provide the required buoyancy. The floating lag time and total floating
time were tested for all the formulations and all formulations showed
consistent total floating time with sustained release profile. The total
floating time is found>11 h across the batches and it is a reflection of
tablets floating time in an acidic media, which mimics the stomach pH
and environment. The total floating time is comparable to the
dissolution release profile with respective formulations of central
composite design.
Table 8: Floating lag time and floating time for formulations of central composite design
Formulation
F1
F2
F3
F4
F5
F6
F7
F8
F9
F10
F11
F12
% Release at 12 h*
97.21±4.02
96.20±3.29
96.11±2.98
94.21±3.55
98.44±4.14
95.01±3.78
96.23±3.33
96.23±5.06
96.74±3.87
95.26±3.64
98.63±2.73
96.55±3.98
Floating lag time (s)
38.00
57.00
102.00
86.00
45.00
64.00
147.00
123.00
41.00
109.00
89.00
65.00
Total floating time (h)
>11.00
>11.00
>11.00
>11.00
>11.00
>11.00
>11.00
>11.00
>11.00
>11.00
>11.00
>11.00
Note: (*mean±SD n=6)
CONCLUSION
The preliminary evaluation has been made to confirm the purity of
valganciclovir hydrochloride. A series of formulation trials has been
conducted and the parameters are evaluated. The valganciclovir
hydrochloride is more soluble in 0.1N Hcl solution and FTIR
confirms drug and excipients are compatible. The in-process
parameters like compressibility index, and flow properties were
found ideal by looking towards the results of friability and hardness.
The dissolution profile found no meaningful difference across the
batches of composition and process robustness trials. This indicates
the minor change in critical material and process attributes has no
major impact on product quality. The optimized formulation is
reproducible and consistent enough to indicate the robustness of
process parameters and formulation composition.
FUNDING
6.
7.
8.
9.
10.
Nil
AUTHORS CONTRIBUTIONS
All the authors have contributed equally
11.
CONFLICT OF INTERESTS
Declared none
12.
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